Drug coated expandable devices

ABSTRACT

Medical devices may be utilized for local and regional therapeutic agent delivery. These therapeutic agents or compounds may reduce a biological organism&#39;s reaction to the introduction of the medical device to the organism. In addition, these therapeutic drugs, agents and/or compounds may be utilized to promote healing, including the prevention of thrombosis. The drugs, agents, and/or compounds may also be utilized to treat specific disorders, including restenosis, vulnerable plaque, and atherosclerosis in type 2 diabetic patients.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 12/059,291 filed Mar. 31, 2008 now U.S. Pat. No. 8,003,122.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the local and/or regionaladministration of therapeutic agents and/or therapeutic agentcombinations, and more particularly to expandable medical devices forthe local and/or regional delivery of therapeutic agents and/ortherapeutic agent combinations for the prevention and treatment ofvascular disease.

2. Discussion of the Related Art

Many individuals suffer from circulatory disease caused by a progressiveblockage of the blood vessels that perfuse the heart and other majororgans. More severe blockage of blood vessels in such individuals oftenleads to hypertension, ischemic injury, stroke, or myocardialinfarction. Atherosclerotic lesions, which limit or obstruct coronaryblood flow, are the major cause of ischemic heart disease. Percutaneoustransluminal coronary angioplasty is a medical procedure whose purposeis to increase blood flow through an artery. Percutaneous transluminalcoronary angioplasty is the predominant treatment for coronary vesselstenosis. The increasing use of this procedure is attributable to itsrelatively high success rate and its minimal invasiveness compared withcoronary bypass surgery. A limitation associated with percutaneoustransluminal coronary angioplasty is the abrupt closure of the vessel,which may occur immediately after the procedure and restenosis, whichoccurs gradually following the procedure. Additionally, restenosis is achronic problem in patients who have undergone saphenous vein bypassgrafting. The mechanism of acute occlusion appears to involve severalfactors and may result from vascular recoil with resultant closure ofthe artery and/or deposition of blood platelets and fibrin along thedamaged length of the newly opened blood vessel.

Restenosis after percutaneous transluminal coronary angioplasty is amore gradual process initiated by vascular injury. Multiple processes,including thrombosis, inflammation, growth factor and cytokine release,cell proliferation, cell migration and extracellular matrix synthesiseach contribute to the restenotic process.

Upon pressure expansion of an intracoronary balloon catheter duringangioplasty and/or stent implantation, smooth muscle cells andendothelial cells within the vessel wall become injured, initiating athrombotic and inflammatory response. Cell derived growth factors suchas platelet derived growth factor, basic fibroblast growth factor,epidermal growth factor, thrombin, etc., released from platelets,invading macrophages and/or leukocytes, or directly from the smoothmuscle cells provoke a proliferative and migratory response in medialsmooth muscle cells. These cells undergo a change from a contractilephenotype to a synthetic phenotype characterized by only a fewcontractile filament bundles, extensive rough endoplasmic reticulum,Golgi and free ribosomes. Proliferation/migration usually begins withinone to two days' post-injury and peaks several days thereafter (Campbelland Campbell, 1987; Clowes and Schwartz, 1985).

Daughter cells migrate to the intimal layer of arterial smooth muscleand continue to proliferate and secrete significant amounts ofextracellular matrix proteins. Proliferation, migration andextracellular matrix synthesis continue until the damaged endotheliallayer is repaired at which time proliferation slows within the intima,usually within seven to fourteen days post-injury. The newly formedtissue is called neointima. The further vascular narrowing that occursover the next three to six months is due primarily to negative orconstrictive remodeling.

Simultaneous with local proliferation and migration, inflammatory cellsadhere to the site of vascular injury. Within three to seven dayspost-injury, inflammatory cells have migrated to the deeper layers ofthe vessel wall. In animal models employing either balloon injury orstent implantation, inflammatory cells may persist at the site ofvascular injury for at least thirty days (Tanaka et al., 1993; Edelmanet al., 1998). Inflammatory cells therefore are present and maycontribute to both the acute and chronic phases of restenosis.

Unlike systemic pharmacologic therapy, stents have proven useful insignificantly reducing restenosis. Typically, stents areballoon-expandable slotted metal tubes (usually, but not limited to,stainless steel), which, when expanded within the lumen of anangioplastied coronary artery, provide structural support through rigidscaffolding to the arterial wall. This support is helpful in maintainingvessel lumen patency. In two randomized clinical trials, stentsincreased angiographic success after percutaneous transluminal coronaryangioplasty, by increasing minimal lumen diameter and reducing, but noteliminating, the incidence of restenosis at six months (Serruys et al.,1994; Fischman et al., 1994).

Additionally, the heparin coating of stents appears to have the addedbenefit of producing a reduction in sub-acute thrombosis after stentimplantation (Serruys et al., 1996). Thus, sustained mechanicalexpansion of a stenosed coronary artery with a stent has been shown toprovide some measure of restenosis prevention, and the coating of stentswith heparin has demonstrated both the feasibility and the clinicalusefulness of delivering drugs locally, at the site of injured tissue.However, in certain circumstances it may not be desirable to leave anytype of implantable device in the body.

Accordingly, there exists a need for drug/drug combinations andassociated local delivery devices for the prevention and treatment ofvascular injury causing intimal thickening which is either biologicallyinduced, for example, atherosclerosis, or mechanically induced, forexample, through percutaneous transluminal coronary angioplasty.

SUMMARY OF THE INVENTION

A device for local and/or regional delivery employing liquidformulations of therapeutic agents in accordance with the presentinvention may be utilized to overcome the disadvantages set forth above.

Medical devices may be utilized for local and regional therapeutic agentdelivery. These therapeutic agents or compounds may reduce a biologicalorganism's reaction to the introduction of the medical device to theorganism. In addition, these therapeutic drugs, agents and/or compoundsmay be utilized to promote healing, including the prevention ofthrombosis. The drugs, agents, and/or compounds may also be utilized totreat specific disorders, including restenosis, vulnerable plaque, andatherosclerosis in type 2 diabetic patients.

The drugs, agents or compounds will vary depending upon the type ofmedical device, the reaction to the introduction of the medical deviceand/or the disease sought to be treated. The type of coating or vehicleutilized to immobilize the drugs, agents or compounds to the medicaldevice may also vary depending on a number of factors, including thetype of medical device, the type of drug, agent or compound and the rateof release thereof.

The present invention is directed to balloons or other inflatable orexpandable devices that may be temporarily positioned within a body todeliver a therapeutic agent and/or continuation of therapeutic agentsand then removed. The therapeutic agents may include liquid formulationsof rapamycin. This type of delivery device may be particularlyadvantageous in the vasculature where stents may not be suitable, forexample, in the larger vessels of the peripheral vascular system.

In use, the balloon or other inflatable or expandable device may becoated with one or more liquid formulations of therapeutic agent(s) anddelivered to a treatment site. The act of inflation or expansion would,force the therapeutic agents into the surrounding tissue. The device maybe kept in position for a period of between ten seconds to about fiveminutes depending upon the location. If utilized in the heart, shorterdurations are required relative to other areas such as the leg.

In accordance with a first aspect, the present invention is directed toa medical device comprising expandable member having a first diameterfor insertion into a vessel and a second diameter for making contactwith the vessel walls, and a liquid formulation of a rapamycin affixedto at least a portion of the surface of the expandable member, theliquid formulation of a rapamycin comprising about 50 mg/ml of arapamycin, about 5 mg/ml of a first excipient selected from the group ofpolymers consisting of PEG 400, PEG 1000, PEG 1500, PEG 2000 andpolyvinyl alcohol, about 5 mg/ml of a second excipient selected from thegroup of antioxidants consisting of BHT, BHA and vitamin E TPGS,ascorbyl palmitate, resveratrol, and acetone and water in a ratio ofabout 60/40 to about 75/25.

In accordance with another aspect, the present invention is directed toa method for coating a device comprising making a liquid formulation ofa rapamycin comprising about 50 mg/ml of a rapamycin, about 5 mg/ml of afirst excipient selected from the group of polymers consisting of PEG400, PEG 100, PEG 1500, PEG 2000 and polyvinyl alcohol, about 5 mg/ml ofa second excipient selected from the group of antioxidants consisting ofBHT, BHA and vitamin E TPGS, ascorbyl palmitate, resveratrol, andacetone and water in a ratio of about 60/40 to about 75/25, coating anexpandable device with the liquid formulation for less than 10 seconds,drying the coated expandable device for about 10 minutes, recoating theexpandable device with the liquid formulation for less than 5 seconds,and drying the recoated expandable device for about 10 minutes.

In accordance with yet another aspect, the present invention is directedto a liquid formulation of a rapamycin comprising about 50 mg/ml of arapamycin, about 50 mg/ml of a first excipient selected from the groupof polymers consisting of PEG 400, PEG 1000, PEG 1500, PEG 2000 andpolyvinyl alcohol, about 5 mg/ml of a second excipient selected from thegroup of antioxidants consisting of BHT, BHA and vitamin E TPGS,ascorbyl palmitate, resveratrol, and acetone and water in a ratio ofabout 60/40 to about 75/25.

In accordance with still another aspect, the present invention isdirected to method for the treatment of vascular disease comprisingpositioning an expandable member having a first unexpanded diameterproximate a treatment site of a diseased vessel, and expanding theexpandable member to a second diameter such that it makes contact withthe vessel walls at the treatment site, the expandable member having acoating comprising about 50 mg/ml of a rapamycin, about 5 mg/ml of afirst excipient selected from the group of polymers consisting of PEG400, PEG 100, PEG 1500, PEG 2000 and polyvinyl alcohol, about 5 mg/ml ofa second excipient selected from the group of antioxidants consisting ofBHT, BHA and vitamin E TPGS, ascorbyl palmitate, resveratrol, andacetone and water in a ratio of about 60/40 to about 75/25, wherein theexpansion of the expandable member to its second diameter facilitatesthe uptake of the liquid formulation into the tissues comprising thevessel walls.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other features and advantages of the invention will beapparent from the following, more particular description of preferredembodiments of the invention, as illustrated in the accompanyingdrawings.

FIG. 1 is a graphical representation of the results of a bioactivitystudy in accordance with the present invention.

FIGS. 2A and 2B illustrate a dip coating process of a PTCA balloon in aliquid formulation of a therapeutic agent in accordance with the presentinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The drug/drug combinations and delivery devices of the present inventionmay be utilized to effectively prevent and treat vascular disease,including vascular disease caused by injury. Various medical treatmentdevices utilized in the treatment of vascular disease may ultimatelyinduce further complications. For example, balloon angioplasty is aprocedure utilized to increase blood flow through an artery and is thepredominant treatment for coronary vessel stenosis. However, theprocedure typically causes a certain degree of damage to the vesselwall, thereby potentially exacerbating the problem at a point later intime. Although other procedures and diseases may cause similar injury,exemplary embodiments of the present invention will be described withrespect to the treatment of restenosis and related complications.

While exemplary embodiments of the invention will be described withrespect to the treatment of restenosis and related complicationsfollowing percutaneous transluminal coronary angioplasty, it isimportant to note that the local delivery of drug/drug combinations maybe utilized to treat a wide variety of conditions utilizing any numberof medical devices, or to enhance the function and/or life of thedevice. For example, intraocular lenses, placed to restore vision aftercataract surgery is often compromised by the formation of a secondarycataract. The latter is often a result of cellular overgrowth on thelens surface and can be potentially minimized by combining a drug ordrugs with the device. Other medical devices which often fail due totissue in-growth or accumulation of proteinaceous material in, on andaround the device, such as shunts for hydrocephalus, dialysis grafts,colostomy bag attachment devices, ear drainage tubes, leads for pacemakers and implantable defibrillators can also benefit from thedevice-drug combination approach. Devices which serve to improve thestructure and function of tissue or organ may also show benefits whencombined with the appropriate agent or agents. For example, improvedosteointegration of orthopedic devices to enhance stabilization of theimplanted device could potentially be achieved by combining it withagents such as bone-morphogenic protein. Similarly other surgicaldevices, sutures, staples, anastomosis devices, vertebral disks, bonepins, suture anchors, hemostatic barriers, clamps, screws, plates,clips, vascular implants, tissue adhesives and sealants, tissuescaffolds, various types of dressings, bone substitutes, intraluminaldevices, and vascular supports could also provide enhanced patientbenefit using this drug-device combination approach. Perivascular wrapsmay be particularly advantageous, alone or in combination with othermedical devices. The perivascular wraps may supply additional drugs to atreatment site. Essentially, any type of medical device may be coated insome fashion with a drug or drug combination which enhances treatmentover use of the singular use of the device or pharmaceutical agent.

In addition to various medical devices, the coatings on these devicesmay be used to deliver therapeutic and pharmaceutic agents including:anti-proliferative/antimitotic agents including natural products such asvinca alkaloids (i.e. vinblastine, vincristine, and vinorelbine),paclitaxel, epidipodophyllotoxins (i.e. etoposide, teniposide),antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin andidarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin, enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents suchas G(GP) II_(b)/III_(a) inhibitors and vitronectin receptor antagonists;anti-proliferative/antimitotic alkylating agents such as nitrogenmustards (mechlorethamine, cyclophosphamide and analogs, melphalan,chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine andthiotepa), alkyl sulfonates-busulfan, nirtosoureas (carmustine (BCNU)and analogs, streptozocin), trazenes-dacarbazinine (DTIC);anti-proliferative/antimitotic antimetabolites such as folic acidanalogs (methotrexate), pyrimidine analogs (fluorouracil, floxuridine,and cytarabine), purine analogs and related inhibitors (mercaptopurine,thioguanine, pentostatin and 2-chlorodeoxyadenosine {cladribine});platinum coordination complexes (cisplatin, carboplatin), procarbazine,hydroxyurea, mitotane, aminoglutethimide; hormones (i.e. estrogen);anti-coagulants (heparin, synthetic heparin salts and other inhibitorsof thrombin); fibrinolytic agents (such as tissue plasminogen activator,streptokinase and urokinase), aspirin, dipyridamole, ticlopidine,clopidogrel, abciximab; antimigratory; antisecretory (breveldin);anti-inflammatory: such as adrenocortical steroids (cortisol, cortisone,fludrocortisone, prednisone, prednisolone, 6α-methylprednisolone,triamcinolone, betamethasone, and dexamethasone), non-steroidal agents(salicylic acid derivatives i.e. aspirin; para-aminophenol derivativesi.e. acetaminophen; indole and indene acetic acids (indomethacin,sulindac, and etodalac), heteroaryl acetic acids (tolmetin, diclofenac,and ketorolac), arylpropionic acids (ibuprofen and derivatives),anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids(piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone),nabumetone, gold compounds (auranofin, aurothioglucose, gold sodiumthiomalate); immunosuppressives: (cyclosporine, tacrolimus (FK-506),sirolimus (rapamycin), azathioprine, mycophenolate mofetil); angiogenicagents: vascular endothelial growth factor (VEGF), fibroblast growthfactor (FGF); angiotensin receptor blockers; nitric oxide donors;antisense oligionucleotides and combinations thereof; cell cycleinhibitors, mTOR inhibitors, and growth factor receptor signaltransduction kinase inhibitors; retenoids; cyclin/CDK inhibitors; HMGco-enzyme reductase inhibitors (statins); and protease inhibitors.

Rapamycin is a macrocyclic triene antibiotic produced by Streptomyceshygroscopicus as disclosed in U.S. Pat. No. 3,929,992. It has been foundthat rapamycin among other things inhibits the proliferation of vascularsmooth muscle cells in vivo. Accordingly, rapamycin may be utilized intreating intimal smooth muscle cell hyperplasia, restenosis, andvascular occlusion in a mammal, particularly following eitherbiologically or mechanically mediated vascular injury, or underconditions that would predispose a mammal to suffering such a vascularinjury. Rapamycin functions to inhibit smooth muscle cell proliferationand does not interfere with the re-endothelialization of the vesselwalls.

Rapamycin reduces vascular hyperplasia by antagonizing smooth muscleproliferation in response to mitogenic signals that are released duringan angioplasty induced injury. Inhibition of growth factor and cytokinemediated smooth muscle proliferation at the late G1 phase of the cellcycle is believed to be the dominant mechanism of action of rapamycin.However, rapamycin is also known to prevent T-cell proliferation anddifferentiation when administered systemically. This is the basis forits immunosuppressive activity and its ability to prevent graftrejection.

The molecular events that are responsible for the actions of rapamycin,a known anti-proliferative, which acts to reduce the magnitude andduration of neointimal hyperplasia, are still being elucidated. It isknown, however, that rapamycin enters cells and binds to a high-affinitycytosolic protein called FKBP12. The complex of rapamycin and FKPB12 inturn binds to and inhibits a phosphoinositide (PI)-3 kinase called the“mammalian Target of Rapamycin” or TOR. TOR is a protein kinase thatplays a key role in mediating the downstream signaling events associatedwith mitogenic growth factors and cytokines in smooth muscle cells and Tlymphocytes. These events include phosphorylation of p27,phosphorylation of p70 s6 kinase and phosphorylation of 4BP-1, animportant regulator of protein translation.

It is recognized that rapamycin reduces restenosis by inhibitingneointimal hyperplasia. However, there is evidence that rapamycin mayalso inhibit the other major component of restenosis, namely, negativeremodeling. Remodeling is a process whose mechanism is not clearlyunderstood but which results in shrinkage of the external elastic laminaand reduction in lumenal area over time, generally a period ofapproximately three to six months in humans.

Negative or constrictive vascular remodeling may be quantifiedangiographically as the percent diameter stenosis at the lesion sitewhere there is no stent to obstruct the process. If late lumen loss isabolished in-lesion, it may be inferred that negative remodeling hasbeen inhibited. Another method of determining the degree of remodelinginvolves measuring in-lesion external elastic lamina area usingintravascular ultrasound (IVUS). Intravascular ultrasound is a techniquethat can image the external elastic lamina as well as the vascularlumen. Changes in the external elastic lamina proximal and distal to thestent from the post-procedural timepoint to four-month and twelve-monthfollow-ups are reflective of remodeling changes.

Evidence that rapamycin exerts an effect on remodeling comes from humanimplant studies with rapamycin coated stents showing a very low degreeof restenosis in-lesion as well as in-stent. In-lesion parameters areusually measured approximately five millimeters on either side of thestent i.e. proximal and distal. Since the stent is not present tocontrol remodeling in these zones which are still affected by balloonexpansion, it may be inferred that rapamycin is preventing vascularremodeling.

The local delivery of drug/drug combinations from a stent has thefollowing advantages; namely, the prevention of vessel recoil andremodeling through the scaffolding action of the stent and theprevention of multiple components of neointimal hyperplasia orrestenosis as well as a reduction in inflammation and thrombosis. Thislocal administration of drugs, agents or compounds to stented coronaryarteries may also have additional therapeutic benefit. For example,higher tissue concentrations of the drugs, agents or compounds may beachieved utilizing local delivery, rather than systemic administration.In addition, reduced systemic toxicity may be achieved utilizing localdelivery rather than systemic administration while maintaining highertissue concentrations. Also in utilizing local delivery from a stentrather than systemic administration, a single procedure may suffice withbetter patient compliance. An additional benefit of combination drug,agent, and/or compound therapy may be to reduce the dose of each of thetherapeutic drugs, agents or compounds, thereby limiting their toxicity,while still achieving a reduction in restenosis, inflammation andthrombosis. Local stent-based therapy is therefore a means of improvingthe therapeutic ratio (efficacy/toxicity) of anti-restenosis,anti-inflammatory, anti-thrombotic drugs, agents or compounds.

A stent is commonly used as a tubular structure left inside the lumen ofa duct to relieve an obstruction. Commonly, stents are inserted into thelumen in a non-expanded form and are then expanded autonomously, or withthe aid of a second device in situ. A typical method of expansion occursthrough the use of a catheter-mounted angioplasty balloon which isinflated within the stenosed vessel or body passageway in order to shearand disrupt the obstructions associated with the wall components of thevessel and to obtain an enlarged lumen.

The data in Table 1 below illustrate that in-lesion percent diameterstenosis remains low in the rapamycin treated groups, even at twelvemonths. Accordingly, these results support the hypothesis that rapamycinreduces remodeling.

TABLE 1.0 Angiographic In-Lesion Percent Diameter Stenosis (%, mean ± SDand “n=”) In Patients Who Received a Rapamycin-Coated Stent Coating Post4-6 month 12 month Group Placement Follow Up Follow Up Brazil 10.6 ± 5.7(30) 13.6 ± 8.6 (30) 22.3 ± 7.2 (15) Netherlands 14.7 ± 8.8 22.4 ± 6.4 —

Additional evidence supporting a reduction in negative remodeling withrapamycin comes from intravascular ultrasound data that was obtainedfrom a first-in-man clinical program as illustrated in Table 2 below.

TABLE 2.0 Matched IVUS data in Patients Who Received a Rapamycin-CoatedStent 4-Month 12-Month Follow-Up Follow-Up IVUS Parameter Post (n=) (n=)(n=) Mean proximal vessel area 16.53 ± 3.53 16.31 ± 4.36 13.96 ± 2.26(mm²) (27) (28) (13) Mean distal vessel area 13.12 ± 3.68 13.53 ± 4.1712.49 ± 3.25 (mm²) (26) (26) (14)

The data illustrated that there is minimal loss of vessel areaproximally or distally which indicates that inhibition of negativeremodeling has occurred in vessels treated with rapamycin-coated stents.

Other than the stent itself, there have been no effective solutions tothe problem of vascular remodeling. Accordingly, rapamycin may representa biological approach to controlling the vascular remodeling phenomenon.

It may be hypothesized that rapamycin acts to reduce negative remodelingin several ways. By specifically blocking the proliferation offibroblasts in the vascular wall in response to injury, rapamycin mayreduce the formation of vascular scar tissue. Rapamycin may also affectthe translation of key proteins involved in collagen formation ormetabolism.

In an exemplary embodiment, the rapamycin is delivered by a localdelivery device to control negative remodeling of an arterial segmentafter balloon angioplasty as a means of reducing or preventingrestenosis. While any delivery device may be utilized, it is preferredthat the delivery device comprises a stent that includes a coating orsheath which elutes or releases rapamycin. The delivery system for sucha device may comprise a local infusion catheter that delivers rapamycinat a rate controlled by the administrator.

Rapamycin may also be delivered systemically using an oral dosage formor a chronic injectible depot form or a patch to deliver rapamycin for aperiod ranging from about seven to forty-five days to achieve vasculartissue levels that are sufficient to inhibit negative remodeling. Suchtreatment is to be used to reduce or prevent restenosis whenadministered several days prior to elective angioplasty with or withouta stent.

Data generated in porcine and rabbit models show that the release ofrapamycin into the vascular wall from a nonerodible polymeric stentcoating in a range of doses (35-430 ug/15-18 mm coronary stent) producesa peak fifty to fifty-five percent reduction in neointimal hyperplasiaas set forth in Table 3 below. This reduction, which is maximal at abouttwenty-eight to thirty days, is typically not sustained in the range ofninety to one hundred eighty days in the porcine model as set forth inTable 4 below.

TABLE 3.0 Animal Studies with Rapamycin-coated stents. Values are mean ±Standard Error of Mean Neointimal % Change From Study Duration Stent¹Rapamycin N Area (mm²) Polyme Metal Porcine 98009 14 days Metal 8 2.04 ±0.17 1X + rapamycin 153 μg 8 1.66 ± 0.17* −42% −19% 1X + TC300 +rapamycin 155 μg 8 1.51 ± 0.19* −47% −26% 99005 28 days Metal 10 2.29 ±0.21 9 3.91 ± 0.60** 1X + TC30 + rapamycin 130 μg 8 2.81 ± 0.34 +23%1X + TC100 + rapamycin 120 μg 9 2.62 ± 0.21 +14% 99006 28 days Metal 124.57 ± 0.46 EVA/BMA 3X 12 5.02 ± 0.62 +10% 1X + rapamycin 125 μg 11 2.84± 0.31* ** −43% −38% 3X + rapamycin 430 μg 12 3.06 ± 0.17* ** −39% −33%3X + rapamycin 157 μg 12 2.77 ± 0.41* ** −45% −39% 99011 28 days Metal11 3.09 ± 0.27 11 4.52 ± 0.37 1X + rapamycin 189 μg 14 3.05 ± 0.35  −1%3X + rapamycin/dex 182/363 μg 14 2.72 ± 0.71 −12% 99021 60 days Metal 122.14 ± 0.25 1X + rapamycin 181 μg 12 2.95 ± 0.38 +38% 99034 28 daysMetal 8 5.24 ± 0.58 1X + rapamycin 186 μg 8 2.47 ± 0.33** −53% 3X +rapamycin/dex 185/369 μg 6 2.42 ± 0.64** −54% 20001 28 days Metal 6 1.81± 0.09 1X + rapamycin 172 μg 5 1.66 ± 0.44  −8% 20007 30 days Metal 92.94 ± 0.43 1XTC + rapamycin 155 μg 10 1.40 ± 0.11*  −52%* Rabbit 9901928 days Metal 8 1.20 ± 0.07 EVA/BMA 1X 10 1.26 ± 0.16  +5% 1X +rapamycin 64 μg 9 0.92 ± 0.14 −27% −23% 1X + rapamycin 196 μg 10 0.66 ±0.12* ** −48% −45% 99020 28 days Metal 12 1.18 ± 0.10 EVA/BMA 1X +rapamycin 197 μg 8 0.81 ± 0.16 −32% ¹Stent nomenclature: EVA/BMA 1X, 2X,and 3X signifies approx. 500 μg, 1000 μg, and 1500 μg total mass(polymer + drug), respectively. TC, top coat of 30 μg, 100 μg, or 300 μgdrug-free BMA; Biphasic; 2 × 1X layers of rapamycin in EVA/BMA spearatedby a 100 μg drug-free BMA layer. ²0.25 mg/kg/d × 14 d preceeded by aloading dose of 0.5 mg/kg/d × 3 d prior to stent implantation. *p < 0.05from EVA/BMA control. ** p < 0.05 from Metal; ^(#) Inflammation score:(0 = essentially no intimal involvement; 1 = <25% intima involved; 2 =≧25% intima involved; 3 = >50% intima involved).

TABLE 4.0 180 day Porcine Study with Rapamycin-coated stents. Values aremean ± Standard Error of Mean Neointimal % Change From InflammationStudy Duration Stent¹ Rapamycin N Area (mm²) Polyme Metal Score # 20007 3 days Metal 10 0.38 ± 0.06 1.05 ± 0.06 (ETP-2-002233-P) 1XTC +rapamycin 155 μg 10 0.29 ± 0.03 −24% 1.08 ± 0.04 30 days Metal 9 2.94 ±0.43 0.11 ± 0.08 1XTC + rapamycin 155 μg 10  1.40 ± 0.11*  −52%* 0.25 ±0.10 90 days Metal 10 3.45 ± 0.34 0.20 ± 0.08 1XTC + rapamycin 155 μg 103.03 ± 0.29 −12% 0.80 ± 0.23 1X + rapamycin 171 μg 10 2.86 ± 0.35 −17%0.60 ± 0.23 180 days  Metal 10 3.65 ± 0.39 0.65 ± 0.21 1XTC + rapamycin155 μg 10 3.34 ± 0.31  −8% 1.50 ± 0.34 1X + rapamycin 171 μg 10 3.87 ±0.28  +6% 1.68 ± 0.37

The release of rapamycin into the vascular wall of a human from anonerodible polymeric stent coating provides superior results withrespect to the magnitude and duration of the reduction in neointimalhyperplasia within the stent as compared to the vascular walls ofanimals as set forth above.

Humans implanted with a rapamycin coated stent comprising rapamycin inthe same dose range as studied in animal models using the same polymericmatrix, as described above, reveal a much more profound reduction inneointimal hyperplasia than observed in animal models, based on themagnitude and duration of reduction in neointima. The human clinicalresponse to rapamycin reveals essentially total abolition of neointimalhyperplasia inside the stent using both angiographic and intravascularultrasound measurements. These results are sustained for at least oneyear as set forth in Table 5 below.

TABLE 5.0 Patients Treated (N = 45 patients) with a Rapamycin-coatedStent Sirolimus FIM 95% Effectiveness Measures (N = 45 Patients, 45Lesions) Confidence Limit Procedure Success (QCA) 100.0% (45/45) [92.1%,100.0%] 4-month In-Stent Diameter Stenosis (%) Mean ± SD (N) 4.8% ± 6.1%(30) [2.6%, 7.0%] Range (min, max) (−8.2%, 14.9%) 6-month In-StentDiameter Stenosis (%) Mean ± SD (N) 8.9% ± 7.6% (13) [4.8%, 13.0%] Range(min, max) (−2.9%, 20.4%) 12-month In-Stent Diameter Stenosis (%) Mean ±SD (N) 8.9% ± 6.1% (15) [5.8%, 12.0%] Range (min, max) (−3.0%, 22.0%)4-month In-Stent Late Loss (mm) Mean ± SD (N) 0.00 ± 0.29 (30) [−0.10,0.10] Range (min, max) (−0.51, 0.45) 6-month In-Stent Late Loss (mm)Mean ± SD (N) 0.25 ± 0.27 (13) [0.10, 0.39] Range (min, max) (−0.51,0.91) 12-month In-Stent Late Loss (mm) Mean ± SD (N) 0.11 ± 0.36 (15)[−0.08, 0.29] Range (min, max) (−0.51, 0.82) 4-month Obstruction Volume(%) (IVUS) Mean ± SD (N) 10.48% ± 2.78% (28) [9.45%, 11.51%] Range (min,max) (4.60%, 16.35%) 6-month Obstruction Volume (%) (IVUS) Mean ± SD (N)7.22% ± 4.60% (13) [4.72%, 9.72%], Range (min, max) (3.82%, 19.88%)12-month Obstruction Volume (%) (IVUS) Mean ± SD (N) 2.11% ± 5.28% (15)[0.00%, 4.78%], Range (min, max) (0.00%, 19.89%) 6-month Target LesionRevascularization (TLR) 0.0% (0/30) [0.0%, 9.5%] 12-month Target LesionRevascularization 0.0% (0/15) [0.0%, 18.1%] (TLR) QCA = QuantitativeCoronary Angiography SD = Standard Deviation IVUS = IntravascularUltrasound

Rapamycin produces an unexpected benefit in humans when delivered from astent by causing a profound reduction in in-stent neointimal hyperplasiathat is sustained for at least one year. The magnitude and duration ofthis benefit in humans is not predicted from animal model data.

These results may be due to a number of factors. For example, thegreater effectiveness of rapamycin in humans is due to greatersensitivity of its mechanism(s) of action toward the pathophysiology ofhuman vascular lesions compared to the pathophysiology of animal modelsof angioplasty. In addition, the combination of the dose applied to thestent and the polymer coating that controls the release of the drug isimportant in the effectiveness of the drug.

As stated above, rapamycin reduces vascular hyperplasia by antagonizingsmooth muscle proliferation in response to mitogenic signals that arereleased during angioplasty injury. Also, it is known that rapamycinprevents T-cell proliferation and differentiation when administeredsystemically. It has also been determined that rapamycin exerts a localinflammatory effect in the vessel wall when administered from a stent inlow doses for a sustained period of time (approximately two to sixweeks). The local anti-inflammatory benefit is profound and unexpected.In combination with the smooth muscle anti-proliferative effect, thisdual mode of action of rapamycin may be responsible for its exceptionalefficacy.

Accordingly, rapamycin delivered from a local device platform, reducesneointimal hyperplasia by a combination of anti-inflammatory and smoothmuscle anti-proliferative effects. Local device platforms include stentcoatings, stent sheaths, grafts and local drug infusion catheters,porous or non-porous balloons or any other suitable means for the insitu or local delivery of drugs, agents or compounds. For example, asset forth subsequently, the local delivery of drugs, agents or compoundsmay be directly from a coating on a balloon.

The anti-inflammatory effect of rapamycin is evident in data from anexperiment, illustrated in Table 6, in which rapamycin delivered from astent was compared with dexamethasone delivered from a stent.Dexamethasone, a potent steroidal anti-inflammatory agent, was used as areference standard. Although dexamethasone is able to reduceinflammation scores, rapamycin is far more effective than dexamethasonein reducing inflammation scores. In addition, rapamycin significantlyreduces neointimal hyperplasia, unlike dexamethasone.

TABLE 6.0 Group Rapamycin Neointimal Area % Area Inflammation Rap N=(mm²) Stenosis Score Uncoated 8 5.24 ± 1.65 54 ± 19 0.97 ± 1.00Dexamethasone 8 4.31 ± 3.02 45 ± 31 0.39 ± 0.24 (Dex) Rapamycin 7  2.47± 0.94*  26 ± 10*  0.13 ± 0.19* (Rap) Rap + Dex 6  2.42 ± 1.58*  26 ±18*  0.17 ± 0.30* *= significance level P < 0.05

Rapamycin has also been found to reduce cytokine levels in vasculartissue when delivered from a stent. The data illustrates that rapamycinis highly effective in reducing monocyte chemotactic protein (MCP-1)levels in the vascular wall. MCP-1 is an example of aproinflammatory/chemotactic cytokine that is elaborated during vesselinjury. Reduction in MCP-1 illustrates the beneficial effect ofrapamycin in reducing the expression of proinflammatory mediators andcontributing to the anti-inflammatory effect of rapamycin deliveredlocally from a stent. It is recognized that vascular inflammation inresponse to injury is a major contributor to the development ofneointimal hyperplasia.

Since rapamycin may be shown to inhibit local inflammatory events in thevessel it is believed that this could explain the unexpected superiorityof rapamycin in inhibiting neointima.

As set forth above, rapamycin functions on a number of levels to producesuch desired effects as the prevention of T-cell proliferation, theinhibition of negative remodeling, the reduction of inflammation, andthe prevention of smooth muscle cell proliferation. While the exactmechanisms of these functions are not completely known, the mechanismsthat have been identified may be expanded upon.

Studies with rapamycin suggest that the prevention of smooth muscle cellproliferation by blockade of the cell cycle is a valid strategy forreducing neointimal hyperplasia. Dramatic and sustained reductions inlate lumen loss and neointimal plaque volume have been observed inpatients receiving rapamycin delivered locally from a stent. Variousembodiments of the present invention expand upon the mechanism ofrapamycin to include additional approaches to inhibit the cell cycle andreduce neointimal hyperplasia without producing toxicity.

The cell cycle is a tightly controlled biochemical cascade of eventsthat regulate the process of cell replication. When cells are stimulatedby appropriate growth factors, they move from G₀ (quiescence) to the G1phase of the cell cycle. Selective inhibition of the cell cycle in theG1 phase, prior to DNA replication (S phase), may offer therapeuticadvantages of cell preservation and viability while retaininganti-proliferative efficacy when compared to therapeutics that act laterin the cell cycle i.e. at S, G2 or M phase.

Accordingly, the prevention of intimal hyperplasia in blood vessels andother conduit vessels in the body may be achieved using cell cycleinhibitors that act selectively at the G1 phase of the cell cycle. Theseinhibitors of the G1 phase of the cell cycle may be small molecules,peptides, proteins, oligonucleotides or DNA sequences. Morespecifically, these drugs or agents include inhibitors of cyclindependent kinases (cdk's) involved with the progression of the cellcycle through the G1 phase, in particular cdk2 and cdk4.

Examples of drugs, agents or compounds that act selectively at the G1phase of the cell cycle include small molecules such as flavopiridol andits structural analogs that have been found to inhibit cell cycle in thelate G1 phase by antagonism of cyclin dependent kinases. Therapeuticagents that elevate an endogenous kinase inhibitory protein^(kip) calledP27, sometimes referred to as P27^(kip1), that selectively inhibitscyclin dependent kinases may be utilized. This includes small molecules,peptides and proteins that either block the degradation of P27 orenhance the cellular production of P27, including gene vectors that cantransfact the gene to produce P27. Staurosporin and related smallmolecules that block the cell cycle by inhibiting protein kinases may beutilized. Protein kinase inhibitors, including the class of tyrphostinsthat selectively inhibit protein kinases to antagonize signaltransduction in smooth muscle in response to a broad range of growthfactors such as PDGF and FGF may also be utilized.

Any of the drugs, agents or compounds discussed herein may beadministered either systemically, for example, orally, intravenously,intramuscularly, subcutaneously, nasally or intradermally, or locally,for example, stent coating, stent covering, local delivery catheter orballoon. In addition, the drugs or agents discussed above may beformulated for fast-release or slow release with the objective ofmaintaining the drugs or agents in contact with target tissues for aperiod ranging from three days to eight weeks.

As set forth above, the complex of rapamycin and FKPB12 binds to andinhibits a phosphoinositide (PI)-3 kinase called the mammalian Target ofRapamycin or TOR. An antagonist of the catalytic activity of TOR,functioning as either an active site inhibitor or as an allostericmodulator, i.e. an indirect inhibitor that allosterically modulates,would mimic the actions of rapamycin but bypass the requirement forFKBP12. The potential advantages of a direct inhibitor of TOR includebetter tissue penetration and better physical/chemical stability. Inaddition, other potential advantages include greater selectivity andspecificity of action due to the specificity of an antagonist for one ofmultiple isoforms of TOR that may exist in different tissues, and apotentially different spectrum of downstream effects leading to greaterdrug efficacy and/or safety.

The inhibitor may be a small organic molecule (approximate mw<1000),which is either a synthetic or naturally derived product. Wortmanin maybe an agent which inhibits the function of this class of proteins. Itmay also be a peptide or an oligonucleotide sequence. The inhibitor maybe administered either sytemically (orally, intravenously,intramuscularly, subcutaneously, nasally, or intradermally) or locally(stent coating, stent covering, local drug delivery catheter). Forexample, the inhibitor may be released into the vascular wall of a humanfrom a nonerodible polymeric stent coating. In addition, the inhibitormay be formulated for fast-release or slow release with the objective ofmaintaining the rapamycin or other drug, agent or compound in contactwith target tissues for a period ranging from three days to eight weeks.

As stated previously, the implantation of a coronary stent inconjunction with balloon angioplasty is highly effective in treatingacute vessel closure and may reduce the risk of restenosis.Intravascular ultrasound studies (Mintz et al., 1996) suggest thatcoronary stenting effectively prevents vessel constriction and that mostof the late luminal loss after stent implantation is due to plaquegrowth, probably related to neointimal hyperplasia. The late luminalloss after coronary stenting is almost two times higher than thatobserved after conventional balloon angioplasty. Conventional balloonangioplasty is distinguished from drug delivery via balloons in that nodrug is imparted by the balloon. Thus, inasmuch as stents prevent atleast a portion of the restenosis process, the use of drugs, agents orcompounds which prevent inflammation and proliferation, or preventproliferation by multiple mechanisms, combined with a stent may providethe most efficacious treatment for post-angioplasty restenosis.

Further, insulin supplemented diabetic patients receiving rapamycineluting vascular devices, such as stents, may exhibit a higher incidenceof restenosis than their normal or non-insulin supplemented diabeticcounterparts. Accordingly, combinations of drugs may be beneficial.

As used herein, rapamycin includes rapamycin and all analogs,derivatives and conjugates that bind to FKBP12, and other immunophilinsand possesses the same pharmacologic properties as rapamycin includinginhibition of TOR.

Although the anti-proliferative effects of rapamycin may be achievedthrough systemic use, superior results may be achieved through the localdelivery of the compound. Essentially, rapamycin works in the tissues,which are in proximity to the compound, and has diminished effect as thedistance from the delivery device increases. In order to take advantageof this effect, one would want the rapamycin in direct contact with thelumen walls.

As described herein, there are a number of advantages to the local orregional delivery of certain drugs, agents and/or compounds via meansother than or in addition to delivery from an implantable medicaldevice. However, the efficacy of the drugs, agents and/or compounds may,to a certain extent, depend on the formulation thereof. The mode ofdelivery may determine the formulation of the drug. Accordingly,different delivery devices may utilize different formulations. Asillustrated above, drugs may be delivered from a stent; however, inother embodiments as described in detail subsequently, any number ofdevices may be utilized.

It is typically very difficult to create solution dosage forms of waterinsoluble and lipohilic (having an affinity for and/or tending tocombine with lipids) drugs such as rapamycin without resorting tosubstantial quantities of surfactants, co-solvents and the like. Oftentimes, these excipients (inert substance that acts as a vehicle), suchas Tween 20 and 80, Cremophor and polyethylene glycol (PEG) come withvarying degrees of toxicity to the surrounding tissue. Accordingly, theuse of organic co-solvents such as dimethol sulfoxide (DMSO),N-methylpyrrolidone (NMP) and ethanol need to be minimized to reduce thetoxicity of the solvent. Essentially, the key for a liquid formulationof a water insoluble drug is to find a good combination of excipient andco-solvent, and an optimal range of the additives in the final dosageform to balance the improvement of drug solubility and necessary safetymargins.

As the outstanding results from clinical trials of recent drug elutingstents such as the Cypher® and Taxus® drug eluting stents demonstrated,a prolonged local high concentration and tissue retention of a potentanti-inflammatory and anti-neoplastic agent released from a stentcoating can substantially eliminate the neointimal growth following anangioplasty procedure. Rapamycin, released from the Cypher® stent hasconsistently demonstrated superior efficacy against restenosis afterstent implantation as compared to a bare metal stent. However, there areclinical situations where a non-stent approach for the local delivery orregional delivery may be advantageous, including bifurcated junctions,small arteries and the restenosis of previously implanted stents.Accordingly, there may exist a need for potent therapeutics that onlyneed to be deposited locally or regionally and the drug will exert itspharmacological functions mainly through its good lipophilic nature andlong tissue retention property.

A locally or regionally delivered solution of a potent therapeuticagent, such as rapamycin, offers a number of advantages over asystemically delivered agent or an agent delivered via an implantablemedical device. For example, a relatively high tissue concentration maybe achieved by the direct deposition of the pharmaceutical agent in thearterial wall. Depending on the location of the deposition, a differentdrug concentration profile may be achieved than through that of a drugeluting stent. In addition, with a locally or regionally deliveredsolution, there is no need for a permanently implanted device such as astent, thereby eliminating the potential side affects associatedtherewith, such as inflammatory reaction and long term tissue damage. Itis, however, important to note that the locally or regionally deliveredsolution may be utilized in combination with drug eluting stents orother coated implantable medical devices. Another advantage of solutionor liquid formulations lies in the fact that the adjustment of theexcipients in the liquid formulation would readily change the drugdistribution and retention profiles. In addition, the liquid formulationmay be mixed immediately prior to the injection through a pre-packagedmulti-chamber injection device to improve the storage and shelf life ofthe dosage forms.

In accordance with exemplary embodiments of the present invention, aseries of liquid formulations were developed for the local or regionaldelivery of water insoluble compounds such as sirolimus and its analogs,including CCI-779, ABT-578 and everolimus, through weeping balloons andcatheter injection needles. Sirolimus and its analogs are rapamycins.These liquid formulations increase the apparent solubility of thepharmacologically active but water insoluble compounds by two to fourorders of magnitude as compared to the solubility limits of thecompounds in water. These liquid formulations rely on the use of a verysmall amount of organic solvents such as Ethanol and a larger amount ofsafe amphiphilic (of or relating to a molecule having a polar, watersoluble group attached to a non-polar, water insoluble hydration chain)excipients such as polyethylene glycol (PEG 200, PEG 400) and vitamin ETPGS to enhance the solubility of the compounds. These liquidformulations of highly water insoluble compounds are stable and readilyflowable at room temperature. Certain excipients, such as Vitamin E TPGSand BHT may be utilized to enhance the storage stability of sirolimuscompounds through their anti-oxidation properties.

Table 7, shown below, summarizes the concentrations of the excipient,the co-solvents and the drug for four different liquid formulations inaccordance with exemplary embodiments of the present invention. Theconcentrations of each constituent were determined by liquidchromatography and are presented as weight by volume figures. As may beseen from Table 7, a 4 mg/ml concentration of sirolimus was achievedwith an ethanol concentration of two percent, a water concentration oftwenty-five percent and a PEG 200 concentration of seventy-five percent.

TABLE 7 Formulation B1 Formulation A1 Sirolimus conc. (mg/mL) 1.79 1.0EtOH conc. (%) 3.83 2 H2O conc. (%) 7.7 25 PEG 200 conc. (%) 88.5 73Sirolimus conc. (mg/mL) 2.0 4 EtOH conc. (%) 2.0 2.0 H2O conc. (%) 25 25PEG 200 conc. (%) 75 75

As set forth above, a liquid formulation comprising 4 mg/ml of sirolimusmay be achieved utilizing PEG 200 as the excipient and ethanol and wateras the co-solvents. This concentration of sirolimus is about fourhundred to about one thousand times higher than the solubility ofsirolimus in water. The inclusion of an effective co-solvent, PEG 200,ensures that the high concentration of sirolimus does not start toprecipitate out of solution until diluted five to ten fold with water.The high concentration of sirolimus is necessary to maintain aneffective and high local concentration of sirolimus after delivery tothe site. The liquid formulations are flowable at room temperature andare compatible with a number of delivery devices. Specifically, each ofthese formulations were successfully injected through an infusioncatheter designated by the brand name CRESCENDO™ from CordisCorporation, Miami, Fla., as described in more detail subsequently, andthe EndoBionics Micro Syringe™ Infusion Catheter available fromEndoBionics, Inc., San Leandros, Calif., as described in more detailabove, in porcine studies.

In another exemplary embodiment, the liquid formulation of sirolimuscomprises water and ethanol as co-solvents and Vitamin E TPGS as theexcipient. The liquid formulation was created utilizing the followingprocess. Two hundred milligrams of sirolimus and two grams of ethanolwere added to a pre-weighed twenty milliliter scintillation vial. Thevial was vortexed and sonicated until the sirolimus was completelydissolved. Approximately six hundred milligrams of Vitamin E TPGS wasthen added to the solution of ethanol and sirolimus. The vial wasvortexed again until a clear yellowish solution was obtained. Nitrogengas was then used to reduce the amount of ethanol in the vial toapproximately two hundred twenty-nine milligrams. In a separate vial,three hundred milligrams of Vitamin E TPGS was dissolved in elevenmilliliters of purified water while undergoing vortexing. The Vitamin ETPGS and water solution was then added to the first vial containing thesirolimus, Vitamin E TPGS and ethanol. The first vial was then vortexedvigorously and continuously for three minutes. The resulting sirolimussolution was clear with a foam on top. The foam gradually disappearedafter sitting at room temperature. An HPLC assay of sirolimus indicatedthat the sirolimus concentration in the final solution was 15 mg/ml. Thefinal solution had an ethanol concentration of less than two percent,which as stated above is important so as to maintain ethanol as aninactive ingredient. Accordingly, utilizing Vitamin E TPGS as theexcipient rather than PEG, resulted in a higher concentration ofsirolimus in the final formulation.

Table 8, as shown below, summarizes the composition and visualobservations for multiple aqueous formulations of sirolimus utilizingethanol, Vitamin E TPGS and water at different ratios. The solutionsrepresented by the data contained in Table 8 were generated usingessentially the same procedure as described above, except that theratios between sirolimus and Vitamin E TPGS were varied.

TABLE 8 13.3 ml water Vitamin E containing Vitamin E Observation ofGroup # Sirolimus mg TPGS, mg Ethanol mg TPGS, mg final solution 1 202.7642 230 320 Clear 2 205.2 631 260 330 Clear 3 201.1 618 260 600 Clear 4204.1 625 260 590 Clear 5 203.3 618 250 1400 Hazy to clear, Viscous 6204.5 630 250 1420 Clear, viscous

All of the above preparations except for number five remained as stablesolutions at both room temperature and under refrigerated condition. Theresults in Table 8 indicate that, Vitamin E TPGS may be utilized over awide range of concentrations to increase the solubility of sirolimus inan aqueous solution.

In another exemplary embodiment, a liquid formulation of CCI-779, asirolimus analog, is prepared utilizing ethanol, Vitamin E TPGS andwater. This liquid formulation was made under similar conditions as tothat described above. Because of its better solubility in ethanol, only0.8 grams of ethanol was used to dissolve two hundred milligrams ofCCI-779 as opposed to the two grams of sirolimus. After the amount ofethanol was reduced to approximately two hundred thirty milligrams,eleven milliliters of purified water containing three hundred milligramsof Vitamin E TPGS was added to the vial of ethanol and CCI-779. Thecombined solution was vortexed for three minutes and resulted in a clearsolution. An HPLC assay of CCI-779 indicated that the concentration ofCCI-779 in the final solution was 15 mg/ml. The concentration of ethanolin the final solution was less than two percent. Accordingly, theresults are substantially identical to that achieved for the sirolimus.

As stated above, a number of catheter-based delivery systems may beutilized to deliver the above-described liquid formulations. One suchcatheter-based system is the CRESCENDO™ infusion catheter. TheCRESCENDO™ infusion catheter is indicated for the delivery of solutions,such as heparinized saline and thrombolytic agents selectively to thecoronary vasculature. The infusion catheter may also be utilized for thedelivery of the liquid formulations, including the liquid solution ofsirolimus, described herein. The infusion region includes an areacomprised of two inflatable balloons with multiple holes at thecatheter's distal tip. The infusion region is continuous with a lumenthat extends through the catheter and terminates at a Luer port in theproximal hub. Infusion of solutions is accomplished by hand injectionthrough an infusion port. The catheter also comprises a guidewire lumenand a radiopaque marker band positioned at the center of the infusionregion to mark its relative position under fluoroscopy.

A larger amount of safe amphiphilic excipients, such as Vitamin E TPGS,PEG 200, and PEG 400, may be used alone or in combination to enhance thesolubility and stability of the drug during the preparation of theformulations. Vitamin E TPGS may also enhance the drug transfer into thelocal tissues during the deployment of the medical device and contactwith a vascular tissue. Enhanced transfer of the drug from the externalsurfaces and subsequent deposition of the drug in the local tissueprovide for a long-term drug effects and positive efficacy such asreduced neointimal formation after an angioplasty procedure or a stentimplantation. In addition to improving the solubility of awater-insoluble drug during the formulation preparation, theseexcipients may also help form a non-crystalline drug formulation on adevice surface when the water is substantially dried off, and facilitatea fast detachment of the drug formulation from the coating of a medicaldevice when contacted with a local tissue.

In addition to infusion catheters, these liquid formulations of highlywater insoluble compounds are stable and may be used for coating anexternal surface of a medical device such as a PTCA balloon.

Alternately, stable solutions, suspensions or emulsions of waterinsoluble compounds may be formed utilizing similar solubility-enhancingagents to obtain a higher drug concentration than the formulations setforth above for coating the external surfaces of a medical device. ThepH value of these suspensions or emulsions may be adjusted to improvethe stability of the drug formulations.

The viscosity of the liquid formulations can be adjusted by changing themixture ratio of PEG and Vitamin E TPGS. Also, additional excipients maybe included without substantially affecting the viscosity of the finalcoating solution but improve the stability of the drug in theformulation and coating.

Although anti-restenotic agents have been primarily described herein,the present invention may also be used to deliver other agents alone orin combination with anti-restenotic agents. Some of the therapeuticagents for use with the present invention which may be transmittedprimarily luminally, primarily murally, or both and may be deliveredalone or in combination include, but are not limited to,antiproliferatives, antithrombins, immunosuppressants includingsirolimus, antilipid agents, anti-inflammatory agents, antineoplastics,antiplatelets, angiogenic agents, anti-angiogenic agents, vitamins,antimitotics, metalloproteinase inhibitors, NO donors, estradiols,anti-sclerosing agents, and vasoactive agents, endothelial growthfactors, estrogen, beta blockers, AZ blockers, hormones, statins,insulin growth factors, antioxidants, membrane stabilizing agents,calcium antagonists, retenoid, bivalirudin, phenoxodiol, etoposide,ticlopidine, dipyridamole, and trapidil alone or in combinations withany therapeutic agent mentioned herein. Therapeutic agents also includepeptides, lipoproteins, polypeptides, polynucleotides encodingpolypeptides, lipids, protein-drugs, protein conjugate drugs, enzymes,oligonucleotides and their derivatives, ribozymes, other geneticmaterial, cells, antisense, oligonucleotides, monoclonal antibodies,platelets, prions, viruses, bacteria, and eukaryotic cells such asendothelial cells, stem cells, ACE inhibitors, monocyte/macrophages orvascular smooth muscle cells to name but a few examples. The therapeuticagent may also be a pro-drug, which metabolizes into the desired drugwhen administered to a host. In addition, therapeutic agents may bepre-formulated as microcapsules, microspheres, microbubbles, liposomes,niosomes, emulsions, dispersions or the like before they areincorporated into the therapeutic layer. Therapeutic agents may also beradioactive isotopes or agents activated by some other form of energysuch as light or ultrasonic energy, or by other circulating moleculesthat can be systemically administered. Therapeutic agents may performmultiple functions including modulating angiogenesis, restenosis, cellproliferation, thrombosis, platelet aggregation, clotting, andvasodilation.

Anti-inflammatories include but are not limited to non-steroidalanti-inflammatories (NSAID), such as aryl acetic acid derivatives, e.g.,Diclofenac; aryl propionic acid derivatives, e.g., Naproxen; andsalicylic acid derivatives, e.g., Diflunisal. Anti-inflammatories alsoinclude glucocoriticoids (steroids) such as dexamethasone, aspirin,prednisolone, and triamcinolone, pirfenidone, meclofenamic acid,tranilast, and nonsteroidal anti-inflammatories. Anti-inflammatories maybe used in combination with antiproliferatives to mitigate the reactionof the tissue to the antiproliferative.

The agents may also include anti-lymphocytes; anti-macrophagesubstances; immunomodulatory agents; cyclooxygenase inhibitors;anti-oxidants; cholesterol-lowering drugs; statins and angiotens inconverting enzyme (ACE); fibrinolytics; inhibitors of the intrinsiccoagulation cascade; antihyperlipoproteinemics; and anti-plateletagents; anti-metabolites, such as 2-chlorodeoxy adenosine (2-CdA orcladribine); immuno-suppressants including sirolimus, everolimus,tacrolimus, etoposide, and mitoxantrone; anti-leukocytes such as 2-CdA,IL-1 inhibitors, anti-CD116/CD18 monoclonal antibodies, monoclonalantibodies to VCAM or ICAM, zinc protoporphyrin; anti-macrophagesubstances such as drugs that elevate NO; cell sensitizers to insulinincluding glitazones; high density lipoproteins (HDL) and derivatives;and synthetic facsimile of HDL, such as lipator, lovestatin,pranastatin, atorvastatin, simvastatin, and statin derivatives;vasodilators, such as adenosine, and dipyridamole; nitric oxide donors;prostaglandins and their derivatives; anti-TNF compounds; hypertensiondrugs including Beta blockers, ACE inhibitors, and calcium channelblockers; vasoactive substances including vasoactive intestinalpolypeptides (VIP); insulin; cell sensitizers to insulin includingglitazones, P par agonists, and metformin; protein kinases; antisenseoligonucleotides including resten-NG; antiplatelet agents includingtirofiban, eptifibatide, and abciximab; cardio protectants including,VIP, pituitary adenylate cyclase-activating peptide (PACAP), apoA-Imilano, amlodipine, nicorandil, cilostaxone, and thienopyridine;cyclooxygenase inhibitors including COX-1 and COX-2 inhibitors; andpetidose inhibitors which increase glycolitic metabolism includingomnipatrilat. Other drugs which may be used to treat inflammationinclude lipid lowering agents, estrogen and progestin, endothelinreceptor agonists and interleukin-6 antagonists, and Adiponectin.

Agents may also be delivered using a gene therapy-based approach incombination with an expandable medical device. Gene therapy refers tothe delivery of exogenous genes to a cell or tissue, thereby causingtarget cells to express the exogenous gene product. Genes are typicallydelivered by either mechanical or vector-mediated methods.

Some of the agents described herein may be combined with additives whichpreserve their activity. For example additives including surfactants,antacids, antioxidants, and detergents may be used to minimizedenaturation and aggregation of a protein drug. Anionic, cationic, ornonionic surfactants may be used. Examples of nonionic excipientsinclude but are not limited to sugars including sorbitol, sucrose,trehalose; dextrans including dextran, carboxy methyl (CM) dextran,diethylamino ethyl (DEAE) dextran; sugar derivatives includingD-glucosaminic acid, and D-glucose diethyl mercaptal; syntheticpolyethers including polyethylene glycol (PEO) and polyvinyl pyrrolidone(PVP); carboxylic acids including D-lactic acid, glycolic acid, andpropionic acid; surfactants with affinity for hydrophobic interfacesincluding n-dodecyl-.beta.-D-maltoside, n-octyl-.beta.-D-glucoside,PEO-fatty acid esters (e.g. stearate (myrj 59) or oleate),PEO-sorbitan-fatty acid esters (e.g. Tween 80, PEO-20 sorbitanmonooleate), sorbitan-fatty acid esters (e.g. SPAN 60, sorbitanmonostearate), PEO-glyceryl-fatty acid esters; glyceryl fatty acidesters (e.g. glyceryl monostearate), PEO-hydrocarbon-ethers (e.g. PEO-10oleyl ether; triton X-100; and Lubrol. Examples of ionic detergentsinclude but are not limited to fatty acid salts including calciumstearate, magnesium stearate, and zinc stearate; phospholipids includinglecithin and phosphatidyl choline; (PC) CM-PEG; cholic acid; sodiumdodecyl sulfate (SDS); docusate (AOT); and taumocholic acid.

Although antioxidants may be utilized with any number of drugs,including all the drugs described herein, exemplary embodiments of theinvention are described with respect to rapamycin and more specifically,drug eluting implantable medical devices comprising rapamycin. Asbriefly set forth above, molecules or specific portions of molecules maybe particularly sensitive to oxidation. In rapamycins, the conjugatedtriene moiety of the molecule is particularly susceptible to oxidation.Essentially, oxygen breaks the carbon chain of the conjugate trienemoiety and the bioactivity of the rapamycin is degraded. In addition, asis typical with oxidation processes, the drug is broken down into one ormore different compounds. Accordingly, it may be particularlyadvantageous to mix or co-mingle an antioxidant with the rapamycin.Specifically, in order to achieve the best results, it is important toco-mingle the antioxidant and the drug to the greatest extent possible.More importantly, the physical positioning of the antioxidant proximateto the drug is the key to success. The antioxidant preferably remainsfree to combine with oxygen so that the oxygen does not break up themoiety and ultimately degrade the drug. Given that the rapamycin may beincorporated into a polymeric coating or matrix, it is particularlyimportant that the antioxidant be maintained proximate to the drugrather than the polymer(s). Factors that influence this include theconstituents of the polymeric matrix, the drug, and how the polymer/drugcoating is applied to the implantable medical device. Accordingly inorder to achieve the desired result, selection of the appropriateantioxidant, the process of mixing all of the elements and theapplication of the mixture is preferably tailored to the particularapplication.

In accordance with exemplary embodiments of the invention, a number ofantioxidants were tested to determine their efficacy in preventing thedegradation of rapamycin, or more specifically, sirolimus. Screeningexperiments were performed to evaluate the solubility of variousantioxidants in tetrahydroxyfuran (THF) solutions containing sirolimusand the percentage of antioxidant required to prevent oxidation ofsirolimus alone and in a basecoat polymeric matrix. THF is the solventin which sirolimus may be dissolved. It is important to note that othersolvents may be utilized. Two sets of controls were utilized. Control #1comprises solutions of THF and sirolimus and/or polymers with noantioxidant, and Control #2 comprises solutions of THF and sirolimusand/or polymers, wherein the THF contains a label claim of 250 ppm ofBHT as a stabilizer from the vendor of THF. In other words, the BHT isan added constituent of the THF solvent to prevent oxidation of thesolvent. Table 9 shown below is a matrix of the various mixtures. Allpercentages are given as weight/volume.

TABLE 9 Antioxidant Target Antioxidant Target Grams/ % Grams/Antioxidant % Antioxidant 50 mL Antioxidant 50 mL Ascorbic 0.02 0.01 0.50.25 Acid Ascorbyl 0.01 0.005 0.02 0.01 Palmitate BHT 0.005 0.0025 0.020.01 Tocopherol 0.05 0.025 0.075 0.0375 Control #1 0.0 0.0 0.0 0.0Control #2 250 ppm BHT 0.0 0.0 0.0

Table 10, shown below, identifies the samples for evaluation. Allpercentages are given as weight/volume. The samples in Table 10 containno polymer. Table 11, also shown below, identifies the samples forevaluation with the solutions now comprising polymers, including PBMAand PEVA.

TABLE 10 Solutions with Sirolimus Only-No Polymers SAMPLE ID # ACTUAL %ANTIOXIDANT AA1A 0.026 Ascorbic Acid AA2A 0.50 Ascorbic Acid AP1A 0.01Ascorbyl Palmitate AP2A 0.02 Ascorbyl Palmitate BHT1A 0.006 BHT BHT2A0.02 BHT C2A Control #2 - 250 ppm BHT TP1A 0.048 Tocopherol TP2A 0.082Tocopherol C1A Control #1

TABLE 11 Solutions with Sirolimus and Polymers SAMPLE ID # ACTUAL %ANTIOXIDANT AA1B 0.022 Ascorbic Acid AA2B 0.508 Ascorbic Acid AP1B 0.01Ascorbyl Palmitate AP2B 0.02 Ascorbyl Palmitate BHT1B 0.006 BHT BHT2B0.02 BHT C2B Control #2 - 250 ppm BHT TP1B 0.054 Tocopherol TP2B 0.102Tocopherol C1B Control #1

As set forth above, each of the samples in Tables 10 and 11 were testedto determine the solubility of the various antioxidants as well as theireffectiveness in preventing drug degradation. All of the antioxidantswere soluble in both the solvent with sirolimus solutions and thesolvent with sirolimus and polymer solutions. The solubility of each ofthe antioxidants was determined by a visual inspection of the testsamples.

Table 12, as shown below, identifies the chosen samples that wereevaluated for drug content (percent label claim or % LC) after five (5)days in an oven set at a temperature of sixty degrees C. (60° C.). Thesamples were evaluated after five (5) days utilizing a drug testingassay for sirolimus. In the exemplary embodiment, a HPLC assay wasutilized. The important numbers are the percent label claim number (%LC) of the solutions that indicates how much of the drug remains or isrecovered. The antioxidants, BHT, Tocopherol, and/or Ascorbic Acidprovided significant protection against the harsh environmentalconditions of the test. Lower % LC numbers are evident in solutionssamples that do not contain an antioxidant.

TABLE 12 Solutions with Sirolimus and Polymers after 5 days 60° C.storage SAMPLE ID # ACTUAL % ANTIOXIDANT % LC AA2B 0.508 Ascorbic Acid96.4 AP2B 0.02 Ascorbyl Palmitate 82.5 BHT2B 0.02 BHT 94.8 TP2B 0.102Tocopherol 97.3 C2B Control #2 - 250 ppm BHT 99.5 C1B Control #1 70.0C1B Control #1 69.2

As shown below, Table 13 provides the % LC results for the sampleswithout polymers and Table 14 provides the % LC results for the sampleswith polymer after four (4) weeks of sixty degrees C. (60° C.).

TABLE 13 CALCULATED THEORETICAL SAMPLE RESULTS CONCENTRATION ID #(μg/ml) (μg/ml) % LC AA1A 1155.56 1669.2 69.2 AA2A 1280.90 1669.2 76.7AP1A 851.45 1669.2 51.0 AP2A 939.36 1669.2 56.3 BHT1A 437.38 1669.2 26.2BHT2A 1434.98 1669.2 86.0 TP1A 1335.58 1669.2 80.0 TP2A 1618.61 1669.297.0 C1A #1 608.64 1669.2 36.5 C1A #2 552.57 1669.2 33.1 C2A #1 1794.701669.2 107.5 C2A #2 1794.67 1669.2 107.5

TABLE 14 CALCULATED THEORETICAL. SAMPLE RESULTS CONCENTRATION ID #(μg/ml) (μg/ml) % LC AA1B 884.95 1669.2 53.0 AA2B 1489.70 1669.2 89.2AP1B 743.98 1669.2 44.6 AP2B 906.76 1669.2 54.3 BHT1B 595.18 1669.2 35.7BHT2B 1396.55 1669.2 83.7 TP1B 1177.30 1669.2 70.5 TP2B 1695.45 1669.2101.6 C1B #1 490.56 1669.2 29.4 C1B #2 470.15 1669.2 28.2 C2B #1 1807.441669.2 108.3 C2B #2 1810.41 1669.2 108.5

As seen from a review of the % LC or drug recovery enumerated in Tables13 and 14, higher percent concentrations of Tocopherol, BHT, and/orAscorbic Acid provide significant protection against the harshenvironmental conditions of the test. However, higher % LC numbers areevident in all controls containing 250 ppm BHT due to possible solutionevaporation of the samples from loose caps on the samples in the 60° C.storage condition.

Additional samples were tested under ambient conditions, rather than at60° C., and using the same compositions; however, the test period wasexpanded to seven weeks. The results are given in Table 15, shown below.

TABLE 15 CALCULATED THEORETICAL SAMPLE RESULTS CONCENTRATION ID #(μg/ml) (μg/ml) % LC C1A 1248.04 1669.2 74.8 C2A 1578.15 1669.2 94.5C1BMS 1376.46 1669.2 82.5 C1BMS 1377.20 1669.2 82.5 C2B 1633.07 1669.297.8 TP1A 1635.54 1669.2 98.0 TP2A 1632.05 1669.2 97.8 TP1B 1631.751669.2 97.8 TP2B 1621.64 1669.2 97.2 AA1A 1590.17 1669.2 95.3 AA2A1578.21 1669.2 94.5 AA1B 1598.79 1669.2 95.8 AA2B 1592.47 1669.2 95.4AP1A 1429.76 1669.2 87.7 AP2A 1415.83 1669.2 84.8 AP1B 1472.45 1669.288.2 AP2B 1480.31 1669.2 88.7 BHT1A 1527.18 1669.2 91.5 BHT2A 1601.721669.2 96.0 BHT1B 1579.50 1669.2 94.6 BHT2B 1614.52 1669.2 96.7

As may be seen from a review of Table 15, the results are substantiallysimilar to those obtained for five (5) days and four (4) weeks at sixtydegrees C. (60° C.) % LC data. Accordingly, in a preferred exemplaryembodiment, Tocopherol, BHT and/or Ascorbic Acid may be utilized tosubstantially reduce drug degradation due to oxidation.

Referring to FIG. 1, there is illustrated in graphical format, theresults of the same drug screening as described above with the solutionapplied to a cobalt-chromium, 18 mm stent. In this test, two sets ofsolution samples were utilized, one with sirolimus and polymer solutioncontaining the antioxidant and one with sirolimus and polymer solutioncontaining no antioxidant. The antioxidant utilized was 0.02 weightpercent BHT per total basecoat solids. The test was utilized todetermine the percent drug content change over a time period of 0 to 12weeks under two conditions; namely, 40° C. with 75 percent relativehumidity, and ambient conditions (25° C.). As can be seen from thechart, the addition of BHT to the solution lessens drug degradation atboth 8 weeks and 12 weeks under ambient conditions. Accordingly, if onedoes not stabilize the base coat solution, other process techniques mustbe utilized; namely, refrigeration and/or vacuum drying.

In accordance with another exemplary embodiment, balloons or otherinflatable or expandable devices may be temporarily positioned within abody to deliver a therapeutic agent and/or combination of therapeuticagents and then removed. The therapeutic agents may include liquidformulations of rapamycins as described above or any other formulationsthereof. This type of delivery device may be particularly advantageousin the vasculature where stents may not be suitable, for example, in thelarger vessels of the peripheral vascular system and at bifurcationpoints in the vasculature, or where the long term scaffolding of a stentis not required or desired.

In use, the balloon or other inflatable or expandable device may becoated with one or more liquid formulations of therapeutic agents(s) anddelivered to a treatment site. The act of inflation or expansion wouldforce the therapeutic agents into the surrounding tissue. The device maybe kept in position for a period of between ten seconds to about fiveminutes depending upon the location. If utilized in the heart, shorterdurations are required relative to other areas such as the leg.

The balloon or other inflatable device may be coated in any suitablemanner including dipping and spraying as described above. In addition,various drying steps may also be utilized. If multiple coats arerequired for a specific dosage, then additional drying steps may beutilized between coats.

In accordance with another embodiment, a solution formulation of arapamycin may be created for use as a coating on the surface of aballoon, as opposed to a stent or through a weeping balloon or infusioncatheter. These formulations have a higher concentration of rapamycinthan those described above.

As set forth herein, aqueous solutions of sirolimus, with solubilityenhancers such as polymers of various molecular weight, PEG 400, PEG1000, PEG 1500, PEG 2000, vitamin E and its derivatives vitamin E TPGS,non-ionic surfactants including Triton X, alky poly(ethylene oxide),Tween 20, Tween 80, and Brij 35. Low molecular weight anionic surfactantsuch as sodium dodecyl sulfate, cationic surfactants such asbenzalkonium chloride, non-ionic surfactants such as lauryl myristate,lauryl palmitate, etc. may be used to create coating solutions oremulsions for balloon coating.

Experimentation is required to obtain the optimal formulations for theparticular coating purpose such that the coating solutions would dry upwithin a required time and the coating morphology would be stable on aballoon surface. But in general, these aqueous formulations areespecially advantageous as a surface balloon coating in that the watercontent in the coating formulations (from 10% water to 90% water in thesolutions) serves to decrease the ability of an organic solvent such asacetone or DMSO to swell and even dissolve the balloons which are madefrom Nylon, Polyester, PBAX and the like. These aqueous solutions willalso cause less damage to the physical and chemical properties ofballoons during and after the coating processes as compared to pureorganic solvent based formulations.

In addition to the solubility enhancers described herein, water miscibleorganic solvents such as ethanol, methanol, acetone, acetonitrile (ACN),methyl ethyl ketone (MEK), dimethylsulfoxide (DMSO) anddimethylformamide (DMF) may be used initially to dissolve the drug andestablish a homogeneous solution before water is added to make a coatingsolution with specific concentrations for use as a surface ballooncoating. A proper titration of the ratio between the organic solvent andwater will also help adjust the concentration of drug in the coatingsolution, amount of coating put on the balloons, drying time for eachcoating steps, and eventually the coating morphology and physicalintegrity of the coating with the drug.

In addition to the solubility enhancers and the organic solventsdescribed herein, other polymeric or non-volatile dissolution enhancingagents may be further added to enhance the formulations. The most usefulones as discussed herein are vitamin E TPGS, polyvinyl alcohol (PVA),microcrystalline cellulose, phospholipids, triglycerides, dextran,heparin and the like. Other antioxidant excipients can also be used inthe formulations to stabilize the sirolimus (rapamycin) in the coating.Such antioxidants include BHT, BHA, vitamin E, vitamin E TPGS, ascorbicacid (vitamin C), ascorbyl palmitate, ascorbyl myristate, resveratroland its many synthetic and semi-synthetic derivatives and analogs, etc.These antioxidant excipients may also serve additional functions such asfacilitating the release of drug coatings from the balloon surface uponcontact with the artery wall. These and other similar excipients willremain in the coating after the drying processes and serve to speed upthe drug in the coating from detaching from the balloon surface at thedisease site. The enhancement of drug coating separation from theballoon through the use of these agents is possibly caused by theirinherent tendency to absorb water upon placement in the physiologicalsituation such as inside the arteries. The swelling and physicalexpansion of the coating at the delivery site will help increase thedelivery efficiency of the drug coating into the diseased arterialtissue. Depending on the nature of the particular excipients they mayalso have the added benefits of enhancing the drug transport from thecoating into the diseased cells and the tissues. For instance,vasodilators such as cilostazol and dipyridamole, may also be used asexcipients to improve the intracellular transport of the drugs. Alsocertain excipients may also enhance the cross-membrane transport andeven sequestration of the drugs into the local tissues.

The balloon coating conditions may also play important roles in creatingthe optimal morphology of the final drug coating in that the dryingspeed of the drug coating matrix on the balloons, the exposure time ofsubsequent coating time (second, third, fourth coatings, etc. if needed)may re-dissolve the previously laid coating layers. A variation of thecurrent invention is that coating formulations with gradually increasingwater content may be used in subsequent coating steps to minimize thecoatings laid down previously and increase coating weight and uniformityof each coating step. The final coating solution may even be an emulsion(high water content, and/or high drug content) as opposed to clearaqueous solutions (high organic solvent content) to complete the coatingprocesses.

The following experiments serve to illustrate the principles andformulations described above. Many of the excipients may be interchangedto enhance one aspect or another of the formulations, without affectingthe efficacy of the particular formulation.

In a first experiment, an aqueous coating solution using PEG 400 and BHTas the solubility and transport enhancers was formulated. To a tared10-ml scintillation vial was added about 100.5 mg of sirolimus(rapamycin, stock # 124623500 batch # RB5070)), followed by about 9.8 mgof PEG 400 (Aldrich), and 10.1 mg of BHT (Aldrich). One ml of ethanolwas then added to dissolve the above components under shaking. Once thesolution became completely clear, 1-ml of water was slowly added to thesolution. The mixed solution became cloudy and sirolimus in the organicsolution was immediately precipitated out. Sirolimus remained insolubleupon agitation. The composition of the coating formulation is shown inTable 16.

TABLE 16 Aqueous coating solution using PEG 400, BHT (A1 formulation)Actual amt Formulation in 2 mL A1 solution Sirolimus conc 50 100.5 mg(mg/ml) PEG 400 (mg/ml) 5 9.8 mg BHT (mg/ml) 5 10.1 mg EtOH (%) 50 1 mlH2O (%) 50 1 ml

No further experimentation on this particular formula was done becauseof the insolubility of the sirolimus.

In a second experiment, an aqueous coating solution using PEG 400 andBHT as the solubility and transport enhancers was formulated. To a tared10-ml scintillation vial was added about 99.0 mg of sirolimus(rapamycin, stock # 124623500 batch # RB5070)), followed by about 10.1mg of PEG 400 (Aldrich), and 9.9 mg of BHT (Aldrich). One and half ml(1.5 ml) of ethanol was then added to dissolve the above componentsunder shaking. Once the solution became completely clear, 0.5-ml ofwater was slowly added to the solution. The mixed solution remainedclear and stable upon agitation. The composition of the coatingformulation is shown in Table 17.

TABLE 17 Aqueous coating solution using PEG 400, BHT (A3) Actual amtFormulation in 2 mL A3 solution Sirolimus conc 50 99 mg (mg/ml) PEG 400(mg/ml) 5 10.1 mg BHT (mg/ml) 5 9.9 mg EtOH (%) 75 1.5 ml H2O (%) 25 0.5ml

The clear solution formulation of Table 17 was transferred to a glassslide for coating morphology studies. A Gilson pipetteman was used totransfer 20 ul of the coating solution onto a pre-weighed glass slidethree times. The coating spots on the slides were allowed to dry at roomtemperature in a laminar hood. The coating spots gradually become opaqueafter drying. The weight of the slides with coated spots were measuredand recorded in lines 1 and 4 of Table 18. The drug content transferefficiency of the coating solution was determined to be approximately 95percent.

TABLE 18 Coating formulations and weight of coated glass slides Tarecoating coating Glass weight wt after weight coat wt solution theorTransfer slide # (g) coating (g) in mg vol (ul) amt (mg) eff (%) Note  1(A3) 4.7626 4.7653 0.0027 2.70 3 × 20 ul 2.85 94.7 clear solution  2(B1) 4.7614 4.7640 0.0026 2.60 3 × 20 ul 2.85 91.2 stable emulsion  3(B1) 4.7444 4.7491 0.0047 4.70 100 ul 4.75 98.9 stable emulsion  4 (A3)4.7665 4.7714 0.0049 4.90 100 ul 4.95 99.0 clear solution  5 (A5) 4.76664.7689 0.0023 2.30 3 × 20 ul 3.03 75.9 partial precipitation  6 (C1)4.7347 4.7371 0.0024 2.40 50 ul 2.51 95.6 clear solution  7 (A5) 4.73674.7397 0.003 3.00 100 ul 5.05 59.4 partial precipitation  8 4.8726discarded  9 (B1) 4.7716 4.7739 0.0023 2.30 50 ul 2.38 96.6 stableemulsion 10 (C1) 4.7646 4.7742 0.0096 4.80 100 ul 5.05 95.0 clearsolution

In a third experiment, an aqueous coating solution using PEG 400 and BHTas the solubility and transport enhancers was formulated. To a tared10-ml scintillation vial was added about 101.0 mg of sirolimus(rapamycin, stock # 124623500 batch # RB5070)), followed by about 10.0mg of PEG 1000 (Aldrich), and 10.2 mg of BHT (Aldrich). One point threeml (1.3 ml) of acetone was then added to dissolve the above componentsunder shaking. Once the solution became completely clear, 0.7-ml ofwater was slowly added to the solution. The mixed solution immediatelybecame cloudy. Upon agitation, part of the drug precipitated out of thesolution and stuck to the vial wall. The composition of the coatingformulation is shown in Table 19.

TABLE 19 Aqueous coating formulation using PEG 1000, BHT (A5) Actual amFormulation in 2 mL A5 solution Sirolimus conc 50 101.0 (mg/ml) PEG 1000(mg/ml) 5 10.0 BHT (mg/ml) 5 10.2 EtOH (%) 65 1.3 H2O 35 0.7

The clear portion of the solution of the formulation of Table 19 wastransferred to a glass slide for coating morphology studies. A Gilsonpipetteman was used to transfer 20 ul of the coating solution onto apre-weighed glass slide three times. The coating spots on the slideswere allowed to dry at room temperature in a laminar hood. The coatingspots gradually become opaque after drying. The weight of the slideswith coated spots were measured and recorded in lines 5 and 7 of Table18. The drug content transfer efficiency of the coating solution wasdetermined to be approximately 76 percent. The decreased efficiency ofdrug transfer was mostly like caused by the precipitation of sirolimusfrom the solution upon the addition of water. This formulation is notsuitable for coating since the weight of final coating is not easilycontrolled.

In a fourth experiment, an aqueous coating solution using PEG 400 andBHT as the solubility and transport enhancers was formulated. To a tared10-ml scintillation vial was added about 95.5 mg of sirolimus(rapamycin, stock # 124623500 batch # RB5070)), followed by about 9.9 mgof PEG 400 (Aldrich), and 10.2 mg of BHT (Aldrich). One point two ml(1.2 ml) of acetone was then added to dissolve the above componentsunder shaking. Once the solution became completely clear, 0.8-ml ofwater was slowly added to the solution. The mixed solution immediatelybecame cloudy and remained as a stable emulsion at room temperature. Thecomposition of the coating formulation is shown in Table 20.

TABLE 20 Aqueous coating formulation using PEG 400, BHT (B1) actual amin Formulation 2 mL B1 solution Sirolimus conc 50 95.5 (mg/ml) PEG 400(mg/ml) 5 9.9 BHT (mg/ml) 5 10.2 Acetone (%) 60 1.2 H2O (%) 40 0.8

The stable emulsion of the formulation of Table 20 was transferred to aglass slide for coating morphology studies. A Gilson pipetteman was usedto transfer 20 ul of the coating solution onto a pre-weighed glass slidethree times. The coating spots on the slides were allowed to dry at roomtemperature in a laminar hood. The coating spots gradually become opaqueafter drying. The weight of the slides with coated spots were measuredand recorded in line 2 of Table 18. Coating solution B1 was similarlytransferred to glass slides with various amounts, with the resultsrecorded in lines 3 and 9 of Table 18, to test the effects of dryingspeed on the coating appearance and morphology. The drug contenttransfer efficiency of the coating solution was determined to be over 90percent. The small transferred amounts in line 2 gave the better coatingmorphology in that the coating membrane is clear, most transparent andeven on the slides. When larger amounts of the coating emulsion weretransferred to the slides, lines 3 and 9, the coating became slightlyopaque. The results suggested that it may be beneficial in the coatingof slides and balloons that multiple passes be utilized to achieve thebest coating morphology and appearances.

In a fifth experiment, an aqueous coating solution using PEG 400 and BHTas the solubility and transport enhancers was formulated. To a tared10-ml scintillation vial was added about 100.5 mg of sirolimus(rapamycin, stock # 124623500 batch # RB5070), followed by about 10.1 mgof PEG 400 (Aldrich), and 9.9 mg of BHT (Aldrich). One point five ml(1.5 ml) of acetone was then added to dissolve the above componentsunder shaking. Once the solution became completely clear, 0.5-ml ofwater was slowly added to the solution. The mixed solution remained aclear and stable solution at room temperature. The composition of thecoating formulation is shown in Table 21.

TABLE 21 Aqueous coating formulation using PEG 400, BHT (C1) Actual amFormulation in 2 mL C1 solution Sirolimus conc 50 100.5 (mg/ml) PEG 100025 10.1 BHT (mg/ml) 5 9.9 Acetone (%) 75 1.5 H2O (%) 25 0.5

The clear solution of the formulation of Table 21 was transferred to aglass slide for coating morphology studies. A Gilson pipetteman was usedto transfer 50 ul of the coating solution onto a pre-weighed glassslide. The coating spot on the slides was allowed to dry at roomtemperature in a laminar hood. The coating spots gradually become opaqueafter drying. The weight of the slides with coated spots were measuredand recorded in line 6 of Table 18. A larger amount of coating solutionC1 was similarly transferred to a glass slide with various amounts,recorded in line 10 Table 18, to test the effects of drying speed on thecoating appearance and morphology. The drug content transfer efficiencyof the coating solution was determined to be over 95 percent. Thisexperiment shows that a higher percentage of an organic solvent(acetone) resulted in a clear solution as compared to the stableemulsion from the fourth experiment. However, the coated membrane turnedout to be hazy and opaque. This morphology is likely due to a fasterdrying speed with a higher percentage of acetone in the coatingsolution, 75 percent, compared to the formulation of the fourthexperiment wherein the acetone percentage was 60 percent. The slightlylower acetone concentration led to a slower drying process and a moreeven and transparent appearance.

In a sixth experiment, an aqueous coating solution using PEG 400, BHT,and PVA as the solubility and transport enhancers was formulated. To atared 10-ml scintillation vial was added about 100.1 mg of sirolimus(rapamycin, stock # 124623500 batch # RB5070), followed by about 10.1 mgof PEG 400 (Aldrich), and 9.9 mg of BHT (Aldrich) and 9.7 poly(vinylalcohol) (PVA, 80% hydrolyzed from Aldrich). One point five ml (1.5 ml)of acetone was then added to dissolve the above components undershaking. Once the solution became completely clear, 0.5-ml of water wasslowly added to the solution. The mixed solution remained a clear andstable solution at room temperature. The composition of the coatingformulation is shown Table 22.

TABLE 22 Aqueous coating formulation using PEG 400, BHT, PVA (C2) Actualam Formulation in 2 mL C2 solution Sirolimus conc 50 100.1 (mg/ml) PEG400 25 10.1 BHT (mg/ml) 5 9.9 PVA (mg/ml) 5 9.7 Acetone (%) 75 1.5 H2O(%) 25 0.5

About 100 ul of the clear solution was transferred to a glass slide toform a membrane. The membrane had a weight of 4.8 mg (96 percenttransfer efficiency) and formed a smooth and even film. Furthermore, a3.0×20 mm PTCA balloon was dipped into the coating solution for tenseconds before being pulled out to dry in the laminar hood. The driedweight of the drug coatings are listed in Table 23. The coating appearedto be translucent to clear. The second dip with about five secondduration increased the weight by another 2.6 mg and the coating becomethicker and more opaque.

TABLE 23 Drug coating weight on balloon surface after dipping coatingTare wt w/1 Net 1 weight (g) coat (g) coat (g) balloon 1 0.0139 0.01690.003 balloon 2 0.0159 0.0188 0.0029 balloon 3 0.0471 0.0511 0.004

The coated balloons were then immersed in deionized water (DI water) fortwo minutes under gentle agitation. The balloons then were clipped to aclamp and placed in a laminar hood to dry for thirty minutes. Thecoating on the balloons became opaque with a white film on the balloon.On average, the coating lost about 14-54 percent drug coating. Theresults are listed below in Table 24.

TABLE 24 Loss of coating weight after immersion in water wt after 1 wtpost water wt removed total % coat (g) soak (g) (g) coat (g) removalballoon 1 0.0169 0.0158 0.0011 0.0077 14.3 balloon 2 0.0188 0.01650.0023 0.0042 54.8 balloon 3 0.0511 0.0488 0.0023 0.0077 29.9

In a seventh experiment, an aqueous coating solution using PEG 400, BHT,PVA and Brij 35 as the solubility and transport enhancers wasformulated. To a tared 10-ml scintillation vial was added about 100.0 mgof sirolimus (rapamycin, stock # 124623500 batch # RB5070), followed byabout 10.1 mg of PEG 400 (Aldrich), and 9.9 mg of BHT (Aldrich) and 10.1poly(vinyl alcohol) (PVA, 80 percent hydrolyzed from Aldrich), and 5.7mg of Brij 35 (Polyoxyethyleneglycol dodecyl ether, a nonionicsurfactant, Aldrich). One point five ml (1.2 ml) of acetone was thenadded to dissolve the above components under shaking. Once the solutionbecame completely clear, 0.8-ml of water was slowly added to thesolution. The mixed solution remained a clear and stable solution atroom temperature. The composition of the coating formulation is shown inTable 25.

TABLE 25 Aqueous coating formulation using PEG 400, BHT, PVA (B2) Actualam Formulation in 2 mL B2 solution Sirolimus conc 50 100.0 (mg/ml) PEG400 25 10.1 BHT (mg/ml) 5 9.9 PVA (mg/ml) 5 10.1 Brij 35 (mg/ml) 2.5 5.7Acetone (%) 60 1.2 H2O (%) 40 0.8

This coating solution was clear, in contrast to the stable emulsion ofB1 from the fourth experiment. This is possibly caused by the additionof PVA and Brij 35 which helps the solubility of sirolimus in the mixedsolution. About 100 ul of the clear solution was transferred to a glassslide to form a membrane. The membrane had a weight of 4.6 mg (92percent transfer efficiency) and formed a smooth and even film.Furthermore, a 3.0×20 mm PTCA balloon was dipped into the coatingsolution for 10 seconds before being pulled out to dry in the laminarhood. The dried weight of the drug coating was 2.2 mg. The coatingappeared to be translucent to clear. The second dip increased the weightby another 3.0 mg and the coating become more opaque. The third dipincreased the coating weight by another 3 mg. Also the speed of thedipping is critical in that prolonged exposure to the coating solutionwill dissolve the previously laid down coating there. The coating weightafter each dipping step and final coating weight were listed in Table26.

TABLE 26 Drug coating weight on balloon surface after dipping coatingtare weight wt w/1 net 1 wt w/2 net 2 wt w/3 net 3 total coat (g) coat(g) coat (g) coat (g) coat (g) coat (g) coat (g) wt (g) balloon 1 0.02340.029 0.0056 0.0308 0.0018 0.0311 0.0003 0.0077 balloon 2 0.018 0.0190.001 0.0196 0.0006 0.0222 0.0026 0.0042 balloon 3 0.0231 0.0255 0.00240.0276 0.0021 0.0308 0.0032 0.0077

From the study it appears that between 4-7 mg of coating was added tothe balloon surface after three dipping steps. The coating appeared tobe clear to translucent.

In the final step of the study, the coating balloons were then immersedin deionized water (DI water) for two minutes under gentle agitation.The balloons then clamped to a clip and were placed in a laminar hood todry for thirty minutes. The coating on the balloons became an opaque andwhite film on the balloon. On average, the coating lost about 70 percentweight as shown in the Table 27.

TABLE 27 Loss of coating weight after immersion in water wt after 3 wtpost water wt removed total % coat (g) soak (g) (g) coat (g) removalballoon 1 0.0311 0.0257 0.0054 0.0077 70.1 balloon 2 0.0222 0.0192 0.0030.0042 71.4 balloon 3 0.0308 0.0256 0.0052 0.0077 67.5

The loss of coating was probably further facilitated by the additionaluse of Brij 35 (surfactant) and PVA (water soluble polymer) whichhydrate upon contact with water. The amount of Brij 35 and PVA in thefinal formulation may be adjusted to control the percent of drug releasefrom the balloon surface.

Some of the above listed aqueous formulations are suitable for use as aPTCA balloon surface coating, especially exemplified by formulations B1,B2, C1, and C2. The various excipients may be adjusted to control thecoating solution for better stability and ease of detachment from theballoon surface upon deployment.

The formulations, B1 and C1 as listed in Table 18, wherein a goodbalance of organic solvent such as acetone and water is reached,together with the optional use of excipients such as PEG, PVA and BHTmay be used to control separation of the drug coating from the balloonsurface. These excipients, by their amphiphilic nature (PEG, Brij 35,and PVA) should also facilitate the transport of drug into the tissueand enhance their tissue retention as well. An additional detachmentfacilitating agent such as PVA and non-ionic surfactant (Brij 35) asused in the formulation set forth in Table 22 for C2, and table 23 forB2 also helped separate the drug coating from the balloon surface.

Accordingly, Table 28 below lists the preferred formulation ranges forsurface coatings based upon the individual formulations B1, B2, C1 andC2 described above.

TABLE 28 Formulation summary B1 C1 B2 C2 Sirolimus conc 50 50 50 50(mg/ml) PEG 400 (mg/ml) 5 5 5 5 BHT (mg/ml) 5 5 5 5 Brij 35 (mg/ml) N/AN/A 2.5 2.5 Acetone/H2O 60/40 75/25 60/40 75/25

It is important to note that the balloon or other medical device may becoated in any suitable manner. For example, the balloon may be spraycoated, have the coating brushed or wiped on, or dip coated. FIG. 2Aillustrates a balloon 200 being dipped into a coating solution,suspension and/or emulsion 202 contained within a vial 204 and FIG. 2Billustrates the coated balloon 206. This process, as described herein,may be repeated multiple times to achieve the desired drugconcentration.

It is important to note that when utilizing a balloon or otherexpandable member to deliver drugs and/or therapeutic agents, theballoon or other expandable member is expanded to a diameter at leastten percent higher than the nominal diameter of the vessel. This overexpansion serves a number of functions, including facilitation of thedrug and/or therapeutic agent into the surrounding tissues. Furthermore,the level and duration of inflation or expansion may influence theextent of drug uptake in the target tissue.

Although shown and described is what is believed to be the mostpractical and preferred embodiments, it is apparent that departures fromspecific designs and methods described and shown will suggest themselvesto those skilled in the art and may be used without departing from thespirit and scope of the invention. The present invention is notrestricted to the particular constructions described and illustrated,but should be constructed to cohere with all modifications that may fallwithin the scope of the appended claims.

What is claimed is:
 1. A medical device comprising: an expandable memberhaving a first diameter for insertion into a vessel and a seconddiameter for making contact with the vessel walls; and a liquidformulation of a rapamycin affixed to at least a portion of the surfaceof the expandable member, the liquid formulation of a rapamycincomprising about 50 mg/ml of a rapamycin, about 5 mg/ml of a firstexcipient selected from the group of polymers consisting of PEG 400, PEG1000, PEG 1500, PEG 2000 and polyvinyl alcohol, about 5 mg/ml of asecond excipient selected from the group of antioxidants consisting ofBHT, BHA and vitamin E TPGS, ascorbyl palmitate, and resveratrol, andacetone and water in a ratio of about 60/40 to about 75/25.
 2. Themedical device according to claim 1 further comprising about 2.5 mg/mlof a third excipient selected from the group of non-ionic surfactantsconsisting of polyoxyethylene lauryl ether, polyoxyethylene (20)sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate,octylphenol ethoxylates, lauryl myristate, and lauryl palmitate.
 3. Themedical device according to claim 1, wherein the expandable membercomprises a balloon.
 4. The medical device according to claim 1, whereinthe liquid formulation is dried to a non-solvent containing compositionto modify the surface of the expandable member.
 5. A method for coatinga device comprising: making a liquid formulation of a rapamycincomprising about 50 mg/ml of a rapamycin, about 5 mg/ml of a firstexcipient selected from the group of polymers consisting of PEG 400, PEG100, PEG 1500, PEG 2000 and polyvinyl alcohol, about 5 mg/ml of a secondexcipient selected from the group of antioxidants consisting of BHT, BHAand vitamin E TPGS, ascorbyl palmitate, and resveratrol, and acetone andwater in a ratio of about 60/40 to about 75/25; coating an expandabledevice with the liquid formulation for less than 10 seconds; drying thecoated expandable device for about 10 minutes; recoating the expandabledevice with the liquid formulation for less than 5 seconds; and dryingthe recoated expandable device for about 10 minutes.
 6. The method forcoating a device according to claim 5, wherein the step of making theliquid formulation further comprises adding a third excipient selectedfrom the group consisting of polyoxyethylene lauryl ether,polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitanmonooleate, octylphenol ethoxylates, lauryl myristate, and laurylpalmitate.
 7. A liquid formulation of a rapamycin comprising about 50mg/ml of a rapamycin, about 50 mg/ml of a first excipient selected fromthe group of polymers consisting of PEG 400, PEG 1000, PEG 1500, PEG2000 and polyvinyl alcohol, about 5 mg/ml of a second excipient selectedfrom the group of antioxidants consisting of BHT, BHA and vitamin ETPGS, ascorbyl palmitate, resveratrol, and acetone arid water in a ratioof about 60/40 to about 75/25.
 8. The liquid formulation of a rapamycinaccording to claim 7 further comprising a third excipient selected fromthe group of non-ionic surfactants consisting of polyoxyethylene laurylether, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20)sorbitan monooleate, octylphenol ethoxylates, lauryl myristate, andlauryl palmitate.
 9. A method for the treatment of vascular diseasecomprising: positioning an expandable member having a first unexpandeddiameter proximate a treatment site of a diseased vessel; and expandingthe expandable member to a second diameter such that it makes contactwith the vessel walls at the treatment site, the expandable memberhaving a coating comprising about 50 mg/ml of a rapamycin, about 5 mg/mlof a first excipient selected from the group of polymers consisting ofPEG 400, PEG 100, PEG 1500, PEG 2000 and polyvinyl alcohol, about 5mg/ml of a second excipient selected from the group of antioxidantsconsisting of BHT, BHA and vitamin E TPGS, ascorbyl palmitate, andresveratrol, and acetone and water in a ratio of about 60/40 to about75/25, wherein the expansion of the expandable member to its seconddiameter facilitates the uptake of the liquid formulation into thetissues comprising the vessel walls.
 10. The liquid formulation of arapamycin according to claim 9 further comprising a third excipientselected from the group of non-ionic surfactants consisting ofpolyoxyethylene lauryl ether, polyoxyethylene (20) sorbitan monolaurate,polyoxyethylene (20) sorbitan monooleate, octylphenol ethoxylates,lauryl myristate, and lauryl palmitate.
 11. The expandable member of themedical device in claim 9 is expanded to a final diameter at thetreatment site that is larger than the nominal diameter of the artery byat least 10 percent.